NSD1 deposits Histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons [RNA-seq]

During postnatal development the DNA methyltransferase DNMT3A deposits high levels of nonCG cytosine methylation in neurons. This unique methylation is critical for transcriptional regulation in the mature mammalian brain, and loss of this mark is implicated in DNMT3Aassociated neurodevelopmental disorders (NDDs). The mechanisms determining genomic nonCG methylation profiles are not well defined however, and it is unknown if this pathway is disrupted in additional NDDs. Here we show that genome topology and gene-expression converge to shape Histone H3 lysine 36 dimethylation (H3K36me2) profiles, which in turn recruit DNMT3A and pattern neuronal non-CG methylation. Brain-specific deletion of NSD1, the H3K36 methyltransferase mutated in the NDD Sotos syndrome, disrupts megabase-scale H3K36me2 patterns, causing alterations in non-CG methylation and transcription that overlap models of DNMT3A disorders. Our findings indicate that H3K36me2 deposited by NSD1 is an important determinant of neuronal non-CG DNA methylation and implicates disruption of this methylation in Sotos syndrome.在出生后发育过程中，DNA甲基转移酶（DNA methyltransferase）DNMT3A可在神经元中沉积高水平的非CG胞嘧啶甲基化。这种独特的甲基化修饰对成熟哺乳动物大脑的转录调控至关重要，而该修饰的缺失与DNMT3A相关神经发育障碍（neurodevelopmental disorders, NDDs）的发生密切相关。然而，目前学界对决定基因组非CG甲基化图谱的分子机制尚不清楚，且尚不明确该通路是否在其他神经发育障碍中发生紊乱。本研究发现，基因组拓扑结构与基因表达共同塑造了组蛋白H3赖氨酸36二甲基化（Histone H3 lysine 36 dimethylation, H3K36me2）的分布模式，而后者可进一步招募DNMT3A，进而调控神经元的非CG甲基化模式。对在神经发育障碍索托斯综合征（Sotos syndrome）中发生突变的H3K36甲基转移酶NSD1进行脑特异性敲除后，会破坏兆碱基级别的H3K36me2分布模式，导致非CG甲基化与转录发生改变，这些改变与DNMT3A紊乱模型的表型高度重合。本研究结果表明，NSD1介导的H3K36me2是神经元非CG DNA甲基化的重要决定因素，并提示该甲基化通路的紊乱参与了索托斯综合征的发病过程。